Preparation Of Nano Drug Delivery System Based On Manganese Dioxide For Relieving Hypoxia And Study On Their Antitumor Effect

Cancer,as a disease with a high morbidity and a high lethality,due to the complexity and susceptibility to metastasis of tumor cells,the existing treatment methods are not effective.In recent years,more and more scientists have come to realize that tumor and tumor microenvironment are an inseparable whole.The tumor microenvironment is like a small ecological environment,which is closely related to the tumor cells in it.Hypoxia is an important feature of tumor microenvironment,which promotes tumor invasion,metastasis and resistance.The lack of O₂ can also cause tumor cells to develop resistance to chemotherapy drugs and limit the effectiveness of photodynamic therapy?PDT?.Manganese dioxide?MnO₂?,as a common catalase,can react with endogenous hydrogen peroxide in tumors to generate oxygen,thereby alleviating the symptoms of tumor hypoxia.In addition,MnO₂ can be degraded to Mn²⁺under acidic conditions,which can be used as a contrast agent for nuclear magnetic imaging,providing a solution for the integration of diagnosis and treatment.In this study,MnO₂,a small particle nanoenzyme,was selected to combine with two kinds of nano-drug carriers,liposome and polydopamine,to construct two different nano-drug-loading systems,and further study the effects of reducing tumor hypoxia on other treatment methods.The specific research contents are as follows:?1?Manganese dioxide encapsulated by paclitaxel and chlorin e6?Ce6?liposomesTherefore,we designed catalase-like nanozymes,manganese dioxide nanoparticles?MnO₂ NPs?,and encapsulated them in liposomes containing paclitaxel?PTX?and chlorin e6?MnO₂-PTX/Ce6@lips?to consume tumor's native H₂O₂ and produce O₂.The large amount of oxygen produced by the MnO₂-PTX/Ce6@lips"burst"the liposomes to achieve a responsive release of the internal drug.Subsequently,O₂ relieved chemoresistanc of tumor cells and provided raw materials for PDT.Finally,MnO₂ NPs were decomposed into Mn²⁺under acidic conditions of lysosome and used as contrast agents for magnetic resonance imaging.The inhibition rate of MnO₂-PTX/Ce6@lips on tumor cells was up to86%under hypoxia state.MnO₂-PTX/Ce6@lips also enhanced efficacy of chemotherapy and PDT in bearing-tumor mice,even reached complete cure.These results suggested great potential of MnO₂-PTX/Ce6@lips for modulation of the TME and enhancement of chemotherapy and PDT along with MRI tracing in the treatment of cancer.?2?Size allosteric light-responsive composite polydopamine?PDA?spheres mediated dual air therapyIn this study,PDA was used as the drug carrier to achieve O₂ and NO dual gas treatment by combining MnO₂ and NO donors.O₂ was used to alleviate tumor hypoxia and reduced the tolerance of tumor cells to drugs.NO could nitrosate mitochondria and DNA to kill tumor cells.Photothermal therapy?PTT?was carried out by PDA loading ICG,and MnO₂ of small particles released by PDA was ablation at high temperature to realize the size alloconfiguration of the drug-carrying system.The designed nanocarriers have a particle size between 100-200nm.By loading hyaluronic acid on the surface,they can be well targeted to the tumor site,and use the EPR effect to achieve tumor site accumulation,which improves the biosafety performance of the drug.After the PDA is dissolved,small particles of MnO₂ can penetrate into the deep tumor cell space,alleviating the problem of deep hypoxia in the tumor.In vivo experiments show that the temperature in mice can reach 50?,which can effectively ablate tumors.As a contrast agent for MRI,Mn²⁺plays an imaging guidance role for treatment.